A more than 30-year-long study is revealing further clues about how HIV hijacks the immune system.
Research published today in mBio, the journal of the American Society for Microbiology, provides yet another theory to explain why a very small number of people with HIV are slow to develop AIDS. Even without medication, some people with HIV can go a decade or longer without enough immune system damage to cause serious illness.
Scientists at the University of Pittsburgh Graduate School of Public Health analyzed data and biological samples from 16 HIV-positive men over the course of 11 years. Eight of them, even without medication, showed little disease progression. The other half showed normal progression.
Among the slowly progressing patients, called "nonprogressors," the researchers found low levels of cholesterol in immune system cells called dendritic cells. They believe that the cholesterol-deprived dendritic cells, which transfer HIV to T-cells, may not be able to do their job. If HIV cannot get to the body's T-cells, also known as CD4 helper cells, the virus has no way to replicate, the scientists hypothesize.
None of the study participants were taking cholesterol-lowering medications, known as statins. The low cholesterol in their immune system cells was the natural result of their genetic makeup.
Professor Charles Rinaldo is the chairman of the University of Pittsburgh's department of Infectious Diseases and Microbiology. He told Healthline that scientists have known for 20 years that if you put “a smidge of virus” in a test tube with dendritic cells, then mix in T-cells, you have “explosive infections.” But if you put the same small amount of the HIV virus into a T-cell directly, it doesn’t replicate well, he said.
Infections flared up even when dendritic cells and T-cells from HIV-negative men were used. But when the researchers mixed HIV with T-cells and dendritic cells from the HIV-positive nonprogressors in a test tube, the virus did not replicate.
“This was striking, and that’s why we took several years to work this up,” Rinaldo said. “It was really almost unbelievable.”
Cholesterol Is Critical for HIV Infection
Rinaldo, who established the Multicenter AIDS Cohort Study (MACS) in Pittsburgh more than three decades ago, has contributed extensively to HIV research. MACS is comprised of 7,000 gay and bisexual men living in Baltimore, Chicago, Pittsburgh, and Los Angeles. The long-term study has allowed scientists to explore how the virus works by including non-infected men as well, some of whom later became HIV-positive.
The University of Pittsburgh scientists found that the nonprogressors had low levels of cholesterol in their dendritic cells even before infection, suggesting that it is a genetic trait. They were also seen to have low cholesterol in their B lymphocyte cells. Rinaldo said his team is now trying to find genetic markers for these traits.
Scientists have long suspected that dendritic cells play a role in infection. But the assumption has been that they participate simply by living in mucus membranes, such as the rectum and vagina, which are common locations of HIV infection.
Scientists have also known for some time that cholesterol is needed for the HIV virus to replicate. Cholesterol is essential for cell function, but the role it plays in HIV infection, specifically, is still unknown.
An HIV Superhighway
Previous research has shown that HIV uses a unique system called tunneling nanotubes, or TNT, to spread among cells. It is a form of cell-to-cell communication that avoids interference by antibodies sent to kill the virus.
“These dendritic cells shoot out long tubes to other dendritic cells,” Rinaldo said. “We think about it as a highway that can take molecules from one cell to another. HIV takes this highway, too.”
Many scientists believe that studying clues hidden in the bodies of nonprogressors will ultimately lead to a cure for the disease, or even a vaccine to give people who don't carry these beneficial gene mutations the same edge over HIV.